RNA triggers chronic stress during neuronal aging

Area of Science:

• Neurobiology
• Cellular Biology
• Molecular Biology

Background:

• Neurodegenerative diseases are associated with disruptions in the integrated stress response (ISR).
• The specific cellular stressors contributing to aging and neurodegeneration remain debated.
• The ISR is crucial for maintaining cellular homeostasis under stress.

Purpose of the Study:

• To identify the source of integrated stress response (ISR) activation in aged neurons.
• To investigate the role of cytoplasmic double-stranded RNA (dsRNA) in ISR activation.
• To explore PKR kinase as a mediator of ISR in aged neurons.

Main Methods:

• Directed transdifferentiation of human fibroblasts into aged neurons.
• Analysis of cytoplasmic dsRNA accumulation and its interaction with PKR.
• Assessment of mitochondrial integrity and dsRNA leakage.
• Evaluation of PKR inhibition effects on cellular stress and translation.

Main Results:

• Increased cytoplasmic dsRNA accumulation activates PKR, triggering the ISR in aged neurons.
• Mitochondrial-derived dsRNA accumulates in aged neurons, binds to PKR, and leaks into the cytoplasm.
• PKR activation leads to dsRNA sequestration in stress granules.
• PKR inhibition reduces cellular stress, restores translation, and normalizes RNA-binding protein expression.

Conclusions:

• Endogenous mitochondrial dsRNA is a key source of RNA stress in aged neurons.
• Dysregulated ISR, mediated by PKR and mitochondrial dsRNA, contributes to neuronal destabilization and neurodegeneration.
• Targeting PKR may offer a therapeutic strategy for neurodegenerative diseases.